Chapter 1: Introduction

Genetics: A Key Discipline of Modern Medicine

In some way, each person is like all others

In some way like a few

In some way unique, like no other.

(Origin unknown)

All humans are equal, and yet so diverse. We share the same genetic information, with the exception of minute differences, yet we differ in our appearance, character, behavior, and health status. Our knowledge about the genetic bases of health status has rapidly changed over the last few years. The completion of the Human Genome Project provided us with a map of the 3 billion base pairs encoding the blueprint of human life. It is now possible to sequence the entire genome of an individual in a single day!

However, while the DNA code of a single human may appear simple, the interpretation of this code for the purpose of understanding the intricacies of health and disease has proven to be tremendously complex. Advancements in molecular biology have determined that factors beyond the genetic code itself—for example, epigenetic regulation and noncoding RNAs—are integral to these processes.

These discoveries, and the ever-expanding availability of clinical assays for genetic traits, have led to the emergence of the relatively new field of “molecular medicine” in which physicians and health care providers apply genetic information to maintain health, rapidly diagnose illness, and solve the problems associated with human disease.

All physicians in this age of molecular medicine must be well versed in the core principles of human genetics, which is the science of the mechanisms and principles through which genetic information determines health and disease. Searching for genetic changes and gene variants within a population, questioning the link between genotype and phenotype, probing the meaning of gene–gene and gene–environment interactions, investigating the role of somatic mutations in the formation of tumors, exploring the possibilities for prenatal diagnostics, and surveying the gene therapy for directed treatment strategies and preventative medicine are relevant for all fields of medicine.

Human genetics serves as an important bridge between basic biology, on one hand, and practical clinical medicine, on the other. It is a “meta-discipline” that permeates all medical specialties. It helps with the diagnosis of a genetic predisposition to the development of a particular illness as well as the interdisciplinary care of affected individuals. It also serves to meet special needs for communicating information about the cause of an illness and its significance in the context of genetic counseling.

The 50 years that span the timeline of early genetic medicine, from the discovery of the DNA double helix by Watson and Crick (in 1953) to the publication of the sequence of 99.99% of the human genome (in 2003), can be thought of as the “pregenomic” period in medical history. As we approach the second decade of the “postgenomic” era, we have a greater appreciation of the complexities regulating the genomic sequence and the importance of understanding these complexities to promote health and cure disease.

Frequency of Genetic Diseases

Genetic diseases occur with varying frequency in all stages of life. It is estimated that, before a pregnancy, up to 50% of all conceptions are lost due to a numeric chromosomal disorder. Of all recognized pregnancies, one-sixth end in a miscarriage, mostly in the first trimester, and 50% to 60% of these are also attributable to a chromosomal aberration.

Genetic diseases contribute significantly to childhood mortality and morbidity rates. While in developing countries 95% of all pediatric hospital admissions are attributable to nongenetic causes (mostly infections), up to 25% of the hospitalized children in developed countries have a genetic disease. At least 50% of all learning disabilities (18 out of 1,000 school-age children) are attributable to genetic factors.

During adulthood cardiovascular diseases and cancer are the most frequent causes of death. Cancer can be considered a genetic disease that is caused by the accumulation of somatic mutations in conjunction with only tentatively known, nonspecific, hereditary genetic variants. In the development of cardiovascular diseases, the interaction of nongenetic and genetic factors plays a central role.

Chromosomal Disorders

Chromosome disorders occur in 0.5% of all newborns. As mentioned previously, this figure is merely “the tip of the iceberg” with regard to all conceptions. Every 10th sperm and every 4th egg cell have an abnormal set of chromosomes. The frequency of individual chromosome disorders varies considerably at different stages of embryonic development. Among aborted fetuses, trisomy 16 represents the most frequent autosomal trisomy; frequently there is a triploidy. Only three autosomal trisomies are viable: 13, 18, and 21. Autosomal monosomies are not viable, whereas monosomy X is viable (it leads to Turner syndrome). Monosomy X is estimated to occur in 1% of all conceptions, yet only 1 in 50 of these children is born alive.

Submicroscopic Chromosomal Anomalies

Many genetic syndromes are caused by losses and gains of chromosomal material below the detection level of light microscopy and involve several or many genes. The recent development of DNA arrays for the genome-wide analysis of copy number variations (CNVs) has led to the discovery of both many more pathogenic variants as well as frequent copy number polymorphisms of uncertain clinical relevance. Bridging the gap between single genes and whole chromosomes, and between polymorphisms and disease-causing mutations, will help bring to light the full impact of CNVs on health and disease.

Single Gene Defects

The data in Table 1.1 refer to the frequency at which these genetic defects become clinically significant. Numerous mutations remain clinically silent throughout an entire life span; however, they may be risk factors for diseases and thus play important roles in the development of multifactorial diseases. For example, it has been shown that 1% of the population carries a mutated allele in the gene coding for the von Willebrand Factor, but in most individuals this causes little or no symptoms. Some genetic variants can be advantageous for the carrier in certain situations; they are part of the normal genetic variability.

Table 1.1.Frequency of Genetic Diseases

Type of Disorder Detection before Age 25 Detection after Age 25 Total Frequency
Chromosome disorders 2:1,000 2:1,000 4:1,000
Single-gene defects 3.5:1,000 16.5:1,000 20:1,000
Multifactorial disorders (with a genetic component) 46:1,000 600:1,000c 646:1,000
Somatic mutations 240:1,000 240:1,000

The frequency of monogenic diseases varies significantly between different geographic regions. Basically, all diseases occur in all populations, yet no disease has the same frequency in all populations. Furthermore, in different populations the same genetic disorder is usually caused by different mutations. The underlying mechanisms for these phenomena, such as new mutation, founder mutation, selection, or genetic drift, are covered in detail in Section 14.3.

Multifactorial Disorders

The vast majority of medical conditions is influenced by genetic factors. Examples of typical multifactorial diseases, where genetic and nongenetic factors work together to varying degrees, are arterial hypertension, rheumatoid arthritis, and dementia. Multifactorial diseases therefore represent the largest group of genetic disorders (during childhood as well as in adulthood).

Somatic Mutations

The genetic makeup of a cell potentially changes with each cell division. Mutations that occur in the germ line (i.e., the path from the zygote to the germ cell of the next generation [in human females not more than 30 mitoses]) are transmitted as new mutations to the offspring and, as the case may be, become visible. Many more mutations arise in somatic cells and contribute to illness.

The best examples of these mutations are neoplastic diseases that typically occur only when several independent somatic mutations work together in one single cell (Section 7.1). Somatic mutations, by definition, are not demonstrable in the entire organism but only in individual tissues (e.g., in a tumor). Somatic mutations play an important role in aging processes and probably in autoimmune diseases.


Somatic mutation:

A mutation that has arisen after conception in somatic cells. It may contribute to illness but is not inherited from the parents and is not passed on to children.

Germline mutation:

A mutation that has arisen after conception in the germ line. It is not inherited from the parents and does not usually contribute to illness, but may be passed on to children (see also: germline mosaicism).

Constitutional mutation:

A mutation that is inherited from the parents, is present in all cells of the body, and may be passed on to children.